The objective of the research program is to determine the molecular properties of monoclonal light chains and the host factors responsible for the light chain-associated renal and systemic diseases which include myeloma (cast) kidney disease, light chain deposition disease, and amyloidosis AL. An integrative basic and clinical research plan is proposed that will utilize our exceptional resource of patients and proteins, and our experience with an in vivo mouse experimental animal model to acquire new knowledge of the pathogenesis and treatment of these diseases. Based on our ability to identify the types of light chains associated with these disease entities and to reproduce, in the mouse model, the clinical and pathological counterparts of these diseases, the specific aims include: (1) Myeloma (tubular cast) kidney disease -to extend our studies on the usefulness of the mouse experimental model for predicting the nephrotoxicity of human Bence Jones proteins; to identify factors that potentiate or prevent the characteristic tubular cast formation and resulting renal failure; and, to determine the protein and host factors responsible for the nephrotoxicity of certain Bence Jones proteins. (2) Light chain deposition disease - to characterize further the properties of the unusual proteins associated with this disease and, using the mouse model, to determine the capacity of Bence Jones proteins to deposit in glomerular and mesangial tissue and in other organs. (3) Amyloidosis AL - to continue to identify and characterize amyloid-associated light chains and proteins extracted from amyloid fibrils, especially those of the V lambda subgroup (V lambda VI) or Vk sub-subgroups (VkIa, VkIIa, and VkIIIa) that we find to be preferentially associated with amyloidosis AL; to expand our clinical and laboratory data base on patients with amyloidosis Al lambda VI, especially those patients found to have pan-myelosis (ie, polycythemia versa); and , based on our ability to induce in the mouse model the human equivalent of amyloidosis AL, to investigate protein and host factors responsible for this fatal disease. The information derived from characterization of monoclonal light chains associated with human light chain-associated renal and systemic diseases (myeloma cast nephropathy, light chain deposition disease, and amyloidosis AL) and the mouse experimental model have important clinical potential for the diagnosis and treatment of patients with these diseases.